PROJECT SUMMARY Cancer has become increasingly treatable as a chronic disease, largely as a result of the rapid expansion of highly effective, targeted anti-cancer therapies, used singly or in combination. Unfortunately, treatment-related cardiovascular (CV) toxicity has emerged as an important contributor to morbidity and mortality in cancer patients. For example, anti-angiogenic tyrosine kinase inhibitors (AA-TKIs) are first-line therapies in metastatic renal cell and thyroid cancers, which have a combined incidence of over 600,000 new cases each year. However, AA-TKIs are also associated with significant CV toxicity, with hypertension in at least half of patients and left ventricular dysfunction in 10 to 15%. Such toxicities can result in dose reductions, treatment interruptions, cessation of necessary therapy, and ultimately worse overall survival. This has resulted in a need to develop evidence-based strategies to mitigate CV toxicity to improve not only CV but also oncologic outcomes. In non-cancer populations, SPRINT demonstrated that intensive systolic blood pressure (SBP) lowering to a target <120mmHg substantially reduces the rate of CV events and all-cause mortality. Though cancer patients who develop CV risk factors such as hypertension or CV disease have worse morbidity and mortality than noncancer comparators, concerns about the tolerability of intensive SBP control limit application of guidelines for aggressive SBP targets in clinical practice. Moreover, patients with cancer were largely excluded from SPRINT. As a result, the optimal SBP target remains unknown among patients receiving targeted cancer therapies. Compelling evidence establishing the impact of intensive SBP control is an important unmet need. Our ultimate objective is to perform a Phase III randomized clinical trial (RCT) to test the hypothesis that intensive SBP lowering to a target of <120 mmHg, as compared to Usual Care, is well-tolerated and beneficial in cancer patients receiving AA-TKIs. The RCT will be performed within the NCI-funded ECOG-ACRIN Cancer Research Group in partnership with the NHLBI-funded Heart Failure Network. This planning grant is designed to inform the design and execution of our Phase III RCT by addressing the following Specific Aims: In Aim 1, we will perform a retrospective analysis to define the distributions of SBP, CV risk scores, incidence of CV events, and all-cause mortality rates in patients treated with AA-TKIs for metastatic renal cell and thyroid cancers. In Aim 2, we will perform a 50-patient prospective pilot study using a site-based cluster randomization design amongst 4 ECOG-ACRIN sites comparing ?Intensive SBP Control? with ?Usual Care.? This will be facilitated by a centralized BP Advisory Core, and will inform the SBP trajectories, safety and tolerability of Intensive SBP control, and participant and site burden. These studies will provide the necessary and sufficient data to launch a Phase III RCT trial that will guide the treatment of hypertension in cancer patients receiving long-term AA-TKI therapy.